Epigenetic-Chronological Age Mismatch Warns of Cancer

Northwestern scientists develop a cancer-risk-predicting algorithm calculating epigenetic age on the basis of blood-based DNA methylation.

Epigenetic age, a new way to measure biological age, is emerging as a way to assess human health and disease at a molecular level. According to scientists based at Northwestern University, epigenetic age may exceed actual age—and if it does, the result may be an increased risk of developing and dying of cancer.

The scientists, led by Lifang Hou, M.D., Ph.D., developed an algorithm to calculate epigenetic age on the basis of blood-based DNA methylation data. The algorithm accounted for 71 DNA methylation markers that could be modified by a person’s environment, including environmental chemicals, exercise, and diet.

The scientists described their work in a study (“Blood Epigenetic Age may Predict Cancer Incidence and Mortality”) that appeared February 15 in the journal EBioMedicine. In this study, the epigenetic-chronological age discrepancy, or Δage, was assessed for its potential as a cancer biomarker.

Although the current study was not the first to consider how epigenetic-chronological age discrepancies related to cancer, it was unusual in tracking the discrepancy over time—in blood samples collected from 1999 to 2013—instead of at a single point in time.

“In a prospective cohort, Δage and its rate of change over time were calculated in 834 blood leukocyte samples collected from 442 participants free of cancer at blood draw,” the authors of the EBioMedicine article wrote. “About 3–5 years before cancer onset or death, Δage was associated with cancer risks in a dose-responsive manner and a one-year increase in Δage was associated with cancer incidence and mortality. Participants with smaller Δage and decelerated epigenetic aging over time had the lowest risks of cancer incidence and mortality.”

For each one-year increase in the discrepancy between chronological and epigenetic ages, there was a 6% increased risk of getting cancer within three years and a 17% increased risk of cancer death within five years. Those who will develop cancer have an epigenetic age about six months older than their chronological age; those who will die of cancer are about 2.2 years older, the study found.

The test that was used in the study is not commercially available, but it is currently being studied by academic researchers, including a team at Northwestern. The test focused on age-dependent CpG sites enriched in pathways that are also involved in carcinogenesis.

“[Our] findings indicate that this may be a viable strategy for developing predictive biomarkers of cancer,” noted the study’s authors. “In addition, our sensitivity analyses found that the association between Δage and cancer is independent of both telomere length and other comorbidities, suggesting Δage as a specific cancer biomarker as well as the possibility that Δage reflects molecular-level aging or carcinogenic processes that are not captured by telomere measurements.”

“People who are healthy have a very small difference between their epigenetic/biological age and chronological age,” said Dr. Hou. “People who develop cancer have a large difference and people who die from cancer have a difference even larger than that. Our evidence showed a clear trend.

“This could become a new early warning sign of cancer. The discrepancy between the two ages appears to be a promising tool that could be used to develop an early detection blood test for cancer.”